Abstract
Background/Objectives
Itch is the most burdensome symptom in atopic dermatitis (AD) and prurigo nodularis (PN) and is associated with significant psychological distress, sleep deprivation and impaired quality of life. Achieving rapid control of itch is expected to minimize symptomatology and disease burden. Nemolizumab, which targets the interleukin 31 (IL‐31) pathway, rapidly relieved itch in Phase 2 trials; thus, a post hoc analysis of four pivotal randomized controlled clinical trials of nemolizumab in AD and PN was performed to further evaluate the improvement of itch over the first 14 days of therapy.
Methods
Data from ARCADIA 1 and 2 in AD (N = 1728) and OLYMPIA 1 and 2 in PN (N = 560) were analysed. Patients reported itch intensity and sleep disturbance daily. Differences in the proportion of itch and sleep responders (patients with ≥4‐point improvement from baseline in peak pruritus numerical rating scale [PP‐NRS] or sleep disturbance [SD‐NRS] score) between nemolizumab and placebo groups were calculated.
Results
Nemolizumab rapidly reduced itch in AD (ARCADIA 1 and 2), with a difference versus placebo in PP‐NRS responders apparent by Day 2 (pooled data: 10.7% vs. 2.9%; 95% CI: 5.6–10.1; p < 0.0001) that steadily increased through Day 14. Nemolizumab also reduced itch rapidly in PN (OLYMPIA 1 and 2); a difference versus placebo occurred by Day 2 (pooled data: 17.2% vs. 3.7%; 95% CI: 6.8–16.7; p < 0.0001). Early improvement (Day 2) was also observed in sleep in nemolizumab‐treated patients. In pooled analyses in AD, 9.9% (nemolizumab) versus 4.6% (placebo; 95% CI: 2.8–7.7; p = 0.0001) were SD‐NRS responders and in PN, 13.4% versus 4.3% (95% CI: 4.0–13.0; p = 0.0013). Itch and sleep response data in individual studies were consistent with the pooled data.
Conclusions
This analysis confirms previously reported data that nemolizumab relieves itch and sleep disturbance by Day 2 in patients with moderate‐to‐severe AD and PN, indicating that targeting the IL‐31 pathway presents an important way to achieve rapid itch response.
Keywords: atopic dermatitis, eczematous disease, interleukin 31, itch, nemolizumab, onset of action, prurigo nodularis, pruritus, sleep disturbance
Plain Language Summary
People with skin diseases such as atopic dermatitis and prurigo nodularis experience itch, which can be severe and can interfere with their daily lives with missed school or work days and psychological well‐being impairment, especially when the itching lasts for a long time as is often the case with these diseases. Itching can also make it hard to sleep. A medicine that quickly stops itching can help people with atopic dermatitis and prurigo nodularis to feel better. Nemolizumab is a medicine that is approved to treat atopic dermatitis and prurigo nodularis and it works fast to stop itching. This study looked at data from four clinical studies of nemolizumab, focusing on how itch changed during the first 14 days of treatment. Patients in the studies who had atopic dermatitis or prurigo nodularis recorded daily in diaries how much itch they felt and how they slept. The researchers found that nemolizumab started working to control itching in just 2 days and patients also slept better. Less itching and better sleep may improve well‐being in people with atopic dermatitis and prurigo nodularis.
Achieving rapid control of itch in atopic dermatitis and prurigo nodularis may minimize symptomatology and disease burden. Analysis of clinical trials in atopic dermatitis and prurigo nodularis showed significantly more patients in nemolizumab versus placebo groups achieved a meaningful clinical response in itch within 48 h, and separation increased with ongoing treatment.
Why was the study undertaken?
Itch is the universal and most burdensome symptom in atopic dermatitis (AD) and prurigo nodularis (PN) and rapid resolution of itch is a key clinical goal.
What does this study add?
This post hoc analysis of four pivotal clinical trials in AD and PN showed nemolizumab rapidly relieves itch (as early as 2 days) and improvement continued throughout the duration of the studies.
What are the implications of this study for disease understanding and/or clinical care?
Nemolizumab, a drug with a novel mechanism of action, has a rapid onset of action on itch associated with improvements in sleep disturbance; together, these outcomes may contribute to better quality of life for patients with AD and PN.
INTRODUCTION
Chronic inflammatory skin diseases such as atopic dermatitis (AD) and prurigo nodularis (PN; also known as chronic prurigo) are characterized by chronic, debilitating itch that can significantly disrupt daily life with sleep deprivation, psychological distress and missed school or work. 1 , 2 , 3 , 4 , 5 Itch is a universal symptom and the most burdensome symptom for patients with these diseases, as it is linked to significant sleep disruption. 6 , 7 Gwillim et al. note that more than 60% of patients with PN and AD self‐reported that itch disturbed their sleep to a ‘great extent’. 8 A large majority of patients (almost 80% of those with PN) report improvement of itch as their most important therapeutic goal. 9 Many clinical trials in AD and PN include assessment of itch as well as assessments of sleep. The itch (peak pruritus) numerical rating scale (PP‐NRS), a unidimensional 11‐point scale (0 = no itch to 10 = worst imaginable itch), is rated as the most useful instrument for assessing itch by both clinicians and patients. 10 Further, a 4‐point improvement in PP‐NRS score is generally accepted by the European Medicines Agency (EMA) and the United States Food and Drug Administration (US FDA) as a meaningful within‐patient threshold to demonstrate treatment effect in AD and PN. 11 , 12
Chronic itch in inflammatory skin conditions like AD and PN is driven by the interleukin‐31 (IL‐31) pathway, with IL‐31 known as the ‘itch’ cytokine for its direct pruritogenic effect. 13 Elevated levels of IL‐31 and its heterodimeric receptor were reported in the skin and serum of patients with AD and PN. 14 IL‐31 is a critical neuroimmune link between TH2 cells and sensory nerves for the generation of T cell‐mediated itch. 15 , 16 IL‐31 acts as a key driver of the itch‐scratch cycle and is therefore a major contributor to the symptomatic burden in pruritic diseases.
Nemolizumab, the first treatment targeting the IL‐31 pathway, is approved for the treatment of both AD and PN in multiple countries. In both phase 2 and phase 3 trials, treatment with nemolizumab led to clinically meaningful and statistically significant improvements in core signs and symptoms of these diseases. 3 , 17 , 18 , 19 Previous data from phase 2 studies with nemolizumab demonstrated rapid itch relief in patients with AD and PN. 18 , 20 This post hoc study analysed the pivotal phase 3 clinical trial dataset to confirm the early onset of itch responses with nemolizumab.
METHODS
This publication presents the results of a post hoc analysis of four international, large‐scale, randomized, controlled clinical trials: ARCADIA 1 and 2 in AD and OLYMPIA 1 and 2 in PN. 3 , 17 , 19 The ARCADIA studies were identical 48‐week, randomized, placebo‐controlled, double‐blind trials in adults and adolescents (≥12 years) with moderate‐to‐severe AD (investigator global assessment [IGA] score of at least 3, Eczema Area and Severity Index [EASI] ≥16 and Body Surface Area [BSA] involved ≥10%) moderate‐to‐severe pruritus with PP‐NRS ≥4, and an inadequate response to topical corticosteroid therapy. OLYMPIA 1 and 2 were studies that included adults with moderate‐to‐severe PN (at least 20 nodules and IGA of 3 or 4) and severe pruritus (PP‐NRS ≥7 at baseline). While the study design in OLYMPIA 1 and 2 was identical, the treatment period with nemolizumab was 24 weeks in OLYMPIA 1 and 16 weeks in OLYMPIA 2. Complete study details are available in Silverberg et al. (Lancet 2024), Kwatra et al. (New England Journal of Medicine 2023) and Ständer et al. (JAMA Dermatology 2025). 3 , 17 , 19
In ARCADIA 1 and 2, nemolizumab 30 mg (with a loading dose of 60 mg) or matching placebo was administered once every 4 weeks in combination with topical background therapy (medium or low topical corticosteroids with or without topical calcineurin inhibitors). In OLYMPIA 1 and 2, nemolizumab was administered in a dose of 30 mg every 4 weeks (with a 60 mg loading dose) or 60 mg every 4 weeks, depending on baseline body weight, with the lower dose used in patients who weighed <90 kg and the higher dose in patients ≥90 kg; patients in the placebo group received matching placebo injections. Background therapy with topical steroids was not allowed in OLYMPIA 1 and 2.
The pivotal studies all included assessments of clinically meaningful reduction in itch (defined as an improvement of ≥4 points from baseline in weekly average PP‐NRS score). ARCADIA 1 and 2 had co‐primary endpoints of IGA success (score of clear/almost clear and ≥2 point improvement from baseline) and at least 75% improvement in EASI from baseline at Week 16. In these studies, improvement of weekly average PP‐NRS ≥4 points was a key secondary endpoint. OLYMPIA 1 and 2 had primary endpoints of itch response (reduction ≥4 on weekly average PP‐NRS) and IGA success at Week 16. Improvement of weekly average sleep disturbance numerical rating scale (SD‐NRS) ≥4 points was a key secondary endpoint in all four studies.
The PP‐NRS tool was validated as a measure of patient‐reported intensity of worst itch in the prior 24 h (scale 0 = no itch to 10 = worst itch imaginable). 21 PP‐NRS was scored daily from baseline through week 16 (and week 24 in PN) and recorded in patient diaries. Clinically relevant change was defined as a change in score from baseline of at least 2–4 points. 21 Sleep disturbance was assessed by change on the SD‐NRS scale, which was validated by Ständer et al. in PN and by Puelles et al. in AD, and a clinically meaningful change was defined as a 4‐point improvement from baseline. 22 , 23
For this post hoc analysis, PP‐NRS/SD‐NRS responders are defined as patients with ≥4‐point improvement in daily PP‐NRS/SD‐NRS from baseline, where baseline is defined as the last non‐missing daily PP‐NRS/SD‐NRS before first dosing. Differences in the proportion of PP‐NRS and SD‐NRS responders between groups in the individual studies were calculated daily for the first 14 days. Data from the two AD studies were also pooled and analyded, as were those from the two PN studies. Unadjusted and strata‐adjusted p‐values for between‐group comparisons are from the Mantel–Haenszel chi‐square test, and strata‐adjusted p‐values from the Cochran–Mantel–Haenszel (CMH) test were used for between‐group comparisons. The p‐values are nominal and do not control the type I error rate, as they were not adjusted for multiple comparisons. Strata‐adjusted 95% confidence interval (CI) of the difference was estimated using Mantel–Haenszel weight, which adjusted for the randomization stratification variables (IGA severity [3 = moderate, 4 = severe] and PP‐NRS [≥7, <7] for AD; analysis centre and body weight at randomization (<90 kg and ≥90 kg) for PN). Both the strata‐adjusted 95% CI and p‐values were reported in the document. The analyses were conducted on the intention‐to‐treat population, which included all randomized participants. If a patient received rescue therapy, the patient's data after the receipt of rescue therapy was considered treatment failure. Patients with missing results were considered non‐responders according to the Non Responder Imputation analysis. All analyses were performed using SAS 9.4 (SAS Institute, Cary, North Carolina, US). Safety data were collected and analysed as described in the primary publications. 3 , 17 , 19
RESULTS
Study population
A total of 1728 patients participated in the ARCADIA studies and 560 patients in the OLYMPIA studies. Patient demographics and disease characteristics were generally well‐balanced between treatment groups across the respective AD and PN studies, as shown in Table 1. While both sexes were well represented in the ARCADIA studies, there was a numerically higher proportion of females in the OLYMPIA studies. The average age of the PN population was higher than that of the AD population. Baseline disease characteristics were as expected for a moderate‐to‐severe patient population, and both PP‐NRS and SD‐NRS average scores at baseline were higher in the PN indication with higher itch due to inclusion criteria.
TABLE 1.
Patient demographics and key disease characteristics in pooled ARCADIA (top) and OLYMPIA (bottom) data.
| ARCADIA 1 and 2 pooled | |||
|---|---|---|---|
| Nemolizumab + TCS/TCI (N = 1142) | Placebo + TCS/TCI (n = 586) | Total (N = 1728) | |
| Sex, n (%) | |||
| Male | 575 (50.4%) | 306 (52.2%) | 881 (51.0%) |
| Female | 567 (49.6%) | 280 (47.8%) | 847 (49.0%) |
| Ethnicity, n (%) | |||
| Hispanic/Latino | 108 (9.5%) | 51 (8.7%) | 159 (9.2%) |
| Not Hispanic or Latino | 1016 (89.0%) | 532 (90.8%) | 1548 (89.6%) |
| Not reported or unknown | 18 (1.6%) | 3 (0.5%) | 21 (1.2%) |
| Race, n (%) | |||
| White | 909 (79.6%) | 471 (80.4%) | 1380 (79.9%) |
| Black or African American | 61 (5.3%) | 38 (6.5%) | 99 (5.7%) |
| Asian | 152 (13.3%) | 69 (11.8%) | 221 (12.8%) |
| Other or mixed | 20 (1.8%) | 8 (1.4%) | 28 (1.6%) |
| Age, years (mean ± SD) | 34.1 ± 16.8 | 34.2 ± 16.3 | 34.1 ± 16.6 |
| Age group, n (%) | |||
| 12–17 years | 176 (15.4%) | 90 (15.4%) | 266 (15.4%) |
| 18–65 years | 899 (78.7%) | 472 (80.5%) | 1371 (79.3%) |
| >65 years | 67 (5.9%) | 24 (4.1%) | 91 (5.3%) |
| Weight, kg (mean ± SD) | 74.9 ± 18.1 | 75.4 ± 19.3 | 75.0 ± 18.5 |
| BMI, kg/m2 (mean ± SD) | 26.0 ± 5.5 | 26.1 ± 6.0 | 26.0 ± 5.7 |
| EASI score (mean ± SD) | 27.6 ± 10.7 | 27.3 ± 10.1 | 27.5 ± 10.5 |
| IGA score, n (%) | |||
| Moderate | 790 (69.2%) | 421 (71.8%) | 1211 (70.1%) |
| Severe | 352 (30.8%) | 165 (28.2%) | 517 (29.9%) |
| Weekly average PP‐NRS (mean ± SD) | 7.1 ± 1.5 | 7.2 ± 1.5 | 7.1 ± 1.5 |
| Weekly average SD‐NRS (mean ± SD) | 5.9 ± 2.2 | 5.7 ± 2.3 | 5.8 ± 2.2 |
| BSA (%) of atopic dermatitis involvement (mean ± SD) | 44.7 ± 19.7 | 44.3 ± 18.9 | 44.6 ± 19.4 |
| SCORAD index (mean ± SD) | 64.5 ± 11.8 | 64.1 ± 12.3 | 64.3 ± 12.0 |
| DLQI (mean ± SD) | 15.0 ± 6.7 | 14.9 ± 6.9 | 15.0 ± 6.8 |
| cDLQI (mean ± SD) | 12.4 ± 6.3 | 12.5 ± 5.6 | 12.5 ± 6.1 |
| OLYMPIA 1 and 2 pooled | |||
|---|---|---|---|
| Nemolizumab (N = 373) | Placebo (N = 187) | Total (N = 560) | |
| Sex, n (%) | |||
| Male | 150 (40.2%) | 76 (40.6%) | 226 (40.4%) |
| Female | 223 (59.8%) | 111 (59.4%) | 334 (59.6%) |
| Ethnicity, n (%) | |||
| Hispanic/Latino | 9 (2.4%) | 12 (6.4%) | 21 (3.8%) |
| Not Hispanic or Latino | 357 (95.7%) | 167 (89.3%) | 524 (93.6%) |
| Not reported or unknown | 7 (1.9%) | 8 (4.3%) | 15 (2.7%) |
| Race, n (%) | |||
| White | 307 (82.3%) | 149 (79.7%) | 456 (81.4%) |
| Black or African American | 23 (6.2%) | 17 (9.1%) | 40 (7.1%) |
| Asian | 33 (8.8%) | 16 (8.6%) | 49 (8.8%) |
| Other or mixed | 9 (2.4%) | 4 (2.1%) | 13 (2.3%) |
| Not reported | 1 (0.3%) | 1 (0.5%) | 2 (0.4%) |
| Age, years (mean ± SD) | 55.6 ± 13.7 | 54.3 ± 14.6 | 55.2 ± 14.0 |
| Weight, kg (mean ± SD) | 83.4 ± 20.2 | 80.8 ± 20.1 | 82.6 ± 20.2 |
| Weight group at baseline ≥90 kg, n (%) | 124 (33.2%) | 53 (28.3%) | 177 (31.6%) |
| IGA score, n (%) | |||
| Moderate | 215 (57.6%) | 110 (58.8%) | 325 (58.0%) |
| Severe | 158 (42.4%) | 77 (41.2%) | 235 (42.0%) |
| Weekly average PP‐NRS (mean ± SD) | 8.5 ± 0.9 | 8.4 ± 1.0 | 8.5 ± 0.9 |
| Weekly average SD‐NRS (mean ± SD) | 7.1 ± 2.3 | 7.1 ± 2.3 | 7.1 ± 2.3 |
| Time since prurigo nodularis diagnosis, months (mean ± SD) | 95.4 ± 93.4 | 104.5 ± 106.6 | 98.4 ± 98.0 |
| Estimated number of lesions (PAS item 2), n (%) | |||
| 20–100 | 244 (65.4%) | 114 (61.0%) | 358 (63.9%) |
| >100 | 129 (34.6%) | 73 (39.0%) | 202 (36.1%) |
| DLQI (mean ± SD) | 16.8 ± 6.9 | 17.0 ± 6.7 | 16.9 ± w6.8 |
Abbreviations: BMI, body mass index; BSA, body surface area; cDLQI, children's dermatology life quality index, DLQI, dermatology life quality index; EASI, eczema area and severity index; IGA, investigator global assessment; N, number of patients in the intention to treat population of each treatment group; n, number of patients with available data; PAS, prurigo activity score; PP‐NRS, peak pruritus numerical rating scale; SCORAD, SCORing Atopid Dermatitis; SD, standard deviation; SD‐NRS, sleep disturbance numerical rating scale; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids.
Efficacy—itch
As shown in Figure 1, in pooled data from ARCADIA 1 and 2, nemolizumab rapidly reduced itch in AD, with a difference in the proportion of PP‐NRS responders between nemolizumab and placebo apparent by Day 2 (10.7% vs. 2.9%; 95% CI = 5.6, 10.1; p < 0.0001). In the OLYMPIA studies of patients with PN, differences between groups also occurred at Dsay 2 (17.2% vs. 3.7% by Day 2; 95% CI = 6.8, 16.7; p < 0.0001, Figure 1). The difference between groups steadily increased until Day 14, when the proportion of responders for nemolizumab and placebo was 25.5% versus 8.9% (95% CI = 13.2, 20.0; p < 0.0001) in ARCADIA trials and 37.0% versus 10.2% (95% CI = 19.7, 32.9; p < 0.0001) in OLYMPIA trials.
FIGURE 1.
Pooled analysis of daily proportion of patients with improvement in PP‐NRS ≥4 points in ARCADIA 1 and 2 (a) and OLYMPIA 1 and 2 (b). Nemolizumab indicated by blue lines, placebo indicated by grey lines. BL, baseline; ITT, intent‐to‐treat; N, total number of patients; NRI, non‐responder imputation; PP‐NRS, peak pruritus numerical rating scale; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids. Percentage (%) are based on the number of patients in each treatment group (N).
Taken individually, each study, ARCADIA 1 and 2 for AD and OLYMPIA 1 and 2 for PN, demonstrated significant PP‐NRS response at Day 2, as shown in Figure 2.
FIGURE 2.
Individual trial data from ARCADIA 1 and 2 (a) and OLYMPIA 1 and 2 (b) of PP‐NRS responders show the consistency of results between studies. BL, baseline; ITT, intent‐to‐treat; N, total number of patients; NRI, non‐responder imputation; PP‐NRS, peak pruritus numerical rating scale; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids. Percentage (%) are based on the number of patients in each treatment group (N).
Efficacy—Sleep disturbance
Figure 3 presents pooled SD‐NRS data for ARCADIA and OLYMPIA. There was separation between groups with the proportion of sleep responders (≥4‐point improvement on SD‐NRS) for nemolizumab and placebo at Day 2 of 9.9% versus 4.6%, respectively (with 95% CI of difference in proportion = 2.8, 7.7; p = 0.0001) in AD patients and 13.4% versus 4.3% (95% CI of difference in proportion = 4.0, 13.0; p = 0.0013) in PN patients. As with the itch data, sleep data in the respective studies (Figure 4) were highly consistent with pooled data.
FIGURE 3.
Pooled sleep responder data for ARCADIA 1 and 2 (a) and OLYMPIA 1 and 2 (b). BL, baseline; ITT, intent‐to‐treat; N, total number of patients; NRI, non‐responder imputation; SD‐NRS, sleep disturbance numerical rating scale; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids. Percentage (%) are based on the number of patients in each treatment group (N).
FIGURE 4.
Individual trial data from ARCADIA 1 and 2 (a) and OLYMPIA 1 and 2 (b) of SD‐NRS responders show the consistency of results between studies. BL, baseline; ITT, intent‐to‐treat; N, total number of patients; NRI, non‐responder imputation; SD‐NRS, sleep disturbance numerical rating scale; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids. Percentage (%) are based on the number of patients in each treatment group (N).
Prediction of efficacy response at week 16
Patients treated with nemolizumab who were PP‐NRS responders at Day 2 were more likely to be PP‐NRS responders at Week 16 compared to those who were non‐responders at Day 2. In the pooled ARCADIA analysis, 60.7% of Day 2 PP‐NRS responders were also responders at Week 16, compared to 39.7% among those who were non‐responders at Day 2. In the pooled OLYMPIA analysis, 79.7% of Day 2 PP‐NRS responders were also responders at Week 16, compared to 52.8% among those who were non‐responders at Day 2.
At Week 16, IGA responses in patients treated with nemolizumab showed a stronger link to Day 2 PP‐NRS response in PN than AD studies. In the pooled ARCADIA analysis, 39.3% of Day 2 PP‐NRS responders and 36.3% of non‐responders at Day 2 achieved IGA response at Week 16. In the pooled OLYMPIA analysis, IGA responder rates at Week 16 were 40.6% for Day 2 PP‐NRS responders and 30.1% for non‐responders at Day 2.
The association between Day 2 PP‐NRS responder rates and EASI75 responses at Week 16 was less defined. In the pooled ARCADIA analysis, 45.9% of patients who were PP‐NRS responders on Day 2 achieved EASI‐75 at Week 16, compared to 42.5% of those who were non‐responders at Day 2.
Safety
Nemolizumab was well tolerated across all trials for AD and PN. Silverberg et al. reported comparable safety profiles between the nemolizumab and placebo groups in ARCADIA 1 and 2 trials in AD. 3 Adverse events were primarily mild or moderate in severity, with only a small proportion of study participants in any group experiencing severe adverse events (2–4%) and no deaths. 3 Similar results were observed in OLYMPIA 1 and 2. 17 , 19
DISCUSSION
Results from the ARCADIA 1 and 2 studies in AD and from OLYMPIA 1 and 2 in PN were highly consistent, demonstrating nemolizumab's rapid and clinically meaningful impact on itch intensity and sleep. Improvement in both itch and sleep disturbance was observed as early as Day 2 in both disease states, with a quarter of AD patients and more than one‐third of PN patients achieving a significant and clinically meaningful response in both outcomes by Day 14. These data are consistent with post hoc analyses of earlier phase 2 data that also showed rapid and sustained improvements in both AD and PN. 18 , 20 Of note, the proportion of PP‐NRS responders at Day 2 was slightly higher in OLYMPIA studies in PN compared to ARCADIA studies in AD. This might be explained by a higher mean PP‐NRS at baseline in OLYMPIA pooled studies compared to ARCADIA pooled studies, mean PP‐NRS 8.5 versus 7.1, respectively. Taken together, the data underscore the key role of IL‐31 in the characteristic symptomatology associated with these chronic inflammatory skin diseases.
Itch is the most burdensome symptom reported by patients with moderate‐to‐severe AD and patients with PN, and rapid improvement in itch intensity is a key treatment goal. 7 Treatments that rapidly reduce itch and provide clinically meaningful improvements in disease severity and patients' quality of life are key in the current treatment landscape for both AD and PN. 3 , 17 , 19
Itch in chronic neuroimmune skin diseases such as AD and PN can lead to the itch‐scratch cycle, which in turn exacerbates disease. 24 , 25 , 26 Chronic itch can severely impact quality of life, in part due to the associated disturbances in sleep patterns. 7 Thus, rapid relief of itch should be a priority in patients with moderate‐to‐severe AD and patients with PN. Newer treatment options that target underlying pathophysiology in these diseases show an ability to relieve itch. In an analysis of the pivotal trials of abrocitinib with daily collection of itch assessments, an oral Janus kinase 1 inhibitor, in patients with moderate‐to‐severe AD (N = 837), Ständer et al. reported that significant itch relief was reached by Day 4 in a greater proportion of patients treated with abrocitinib 200 mg (18.6%) than those treated with dupilumab (5.6%, p < 0.001) and placebo (6.0%, p < 0.003). 27 Similarly, daily analysis of upadacitinib showed separation of itch responders from placebo within the first 72 h, depending on the dose, in the Measure Up 1 and 2 studies in AD. 28 In a pooled analysis of dupilumab SOLO, CHRONOS and AD ADOL—which to our knowledge did not collect daily itch scores in a similar fashion as the other studies—studies with 1505 patients with AD, the proportion of itch responders based on PP‐NRS 4 point reduction in the dupilumab groups separated from the placebo group at Day 4 (p < 0.01) in SOLO pooled studies and Day 7 (p < 0.05) in the AD ADOL study. 29 In the dupilumab PRIME studies in PN (N = 311), no data based on daily itch responses are currently available. However, separation in itch response based on weekly average Worst Itch NRS 4‐point reduction between dupilumab 300 mg and placebo occurred at week 3 (PRIME) and week 4 (PRIME 2). 30 The fast onset of action on itch with nemolizumab is linked to its specific mechanism of action targeting IL‐31 signalling through IL‐31 receptor alpha inhibition that is the main driver of itch. 31
A key strength of this analysis is that the data analysed are from large, randomized placebo‐controlled studies with blinded assessment of pruritus and sleep disturbance using validated patient‐reported outcome measures. A limitation of this analysis is its post hoc nature because the endpoint was not pre‐specified for formal hypothesis testing in the statistical analysis plan. However, the observed treatment effects in two different diseases (AD and PN) and the associated 95% CIs indicate a clinically meaningful and precise signal of rapid onset.
CONCLUSIONS
In conclusion, the findings of this post hoc analysis confirm that nemolizumab has a rapid onset of action in relieving itch (by Day 2) as well as improving sleep in patients with moderate‐to‐severe AD and PN. This indicates that targeting the IL‐31 pathway may represent an important approach to achieving rapid itch response.
AUTHOR CONTRIBUTIONS
All authors met the ICMJE authorship criteria.
FUNDING INFORMATION
All studies were sponsored by Galderma.
CONFLICT OF INTEREST STATEMENT
Dr Ständer was speaker and/or consultant and/or investigator and/or has received research funding from Almirall S. A., Amgen Inc., Amgen Europe GmbH, Celldex Therapeutics Inc., Clexio Biosciences Ltd., Focus‐Insight Healthtech Group Co. Ltd., Galderma Laboratorium GmbH, Galderma R&D LLC, Galderma S.A., GSK R&D Ltd., Incyte Corporation, Klirna Biotech Inc., Leo Pharma, Lilly Deutschland GmbH, Novartis Pharma GmbH, Sanofi‐Aventis Deutschland GmbH, Sanofi‐Aventis R&D, Sanofi‐Genzyme Corporation, TouchIME and Vifor Pharma Deutschland GmbH P. G. Unna Academy. Dr Elmariah has served as an advisory board member or consultant for Bambusa Therapeutics, Celldex Therapeutics, Disc Medicine, Galderma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi; an investigator for Celldex and Galderma; scientific co‐founder and advisor for New Frontier Bio. Dr Kwatra has served as a researcher/investigator for Regeneron Pharmaceuticals and Incyte Corporation (paid to his institution) and as a consultant/advisor/speaker for AbbVie, Amgen, Arcutis Biotherapeutics, Aslan Pharmaceuticals, Alphyn Biologics, Cara Therapeutics, Castle Biosciences, Celldex Therapeutics, Dermavant Sciences, Eli Lilly & Company, Galderma, E.R. Squibb and Sons, Genzada Pharmaceuticals, Genzyme Corporation, Incyte Corporation, Janssen Scientific Affairs, Johnson & Johnson, Leo Pharma, Novartis Pharmaceuticals Corporation, Pfizer, Regeneron Pharmaceuticals and Sanofi‐Aventis. Dr Kwatra is the National Secretary and Treasurer for the Skin of Colour Society and Councillor of the National Eczema Association's Scientific and Medical Advisory Council. Dr Yosipovitch has served as an advisory board member consultant for AbbVie, Arcutis, Almiral, Amgen, Attovia Celldex, Escient Health, Eli Lilly, Galderma, LEO Pharma, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, Vifor, GSK, Celldex and as an investigator or received research support from AbbVie, Celldex, Clexio, Eli Lilly, Escient Health, Galderma, Kiniska, LEO Pharma, Novartis, Pfizer, Regeneron and Sanofi. Dr Pink has received research grants from Pfizer, Medac and Amgen; has served as a consultant/advisor/speaker for AbbVie, Pfizer, Galderma, Lilly, Leo, Almirall, Amgen, Sanofi, Novartis, UCB, Bristol Myer Squibb, Johnson & Johnson and Boehringer Ingleheim; and has received educational support from AbbVie, Lilly, Leo, Amgen, Sanofi, Novartis, UCB and Johnson & Johnson. Dr Silverberg has received grants from Galderma and Pfizer (paid to his institution); and has received honoraria as a consultant and/or advisory board member from AbbVie, Afyx, Aobiome, Arena, Asana, Aslan, BioMX, Bluefin, Bodewell, Boehringer‐Ingelheim, Celgene, Connect Biopharma, Dermavant, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Kiniksa, LEO Pharma, Luna, Menlo, Novartis, Pfizer, RAPT, Regeneron and Sanofi‐Genzyme and as a speaker from AbbVie, Eli Lilly, LEO Pharma, Pfizer, Regeneron and Sanofi‐Genzyme. Dr Cheong, Dr Chen, Dr Piketty, Dr Jabbar‐Lopez and Dr Ulianov are employees of Galderma.
ETHICAL APPROVAL
All procedures in the four original studies were initiated after approval from applicable regulatory authorities and independent ethics committees/institutional review boards (according to institution and/or country requirements) and followed Good Clinical Practice Guidelines, the Declaration of Helsinki and International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use Guidelines. The trials were registered at ClinicalTrials.gov: ARCADIA 1, NCT03985943; ARCADIA 2, NCT03989349; OLYMPIA 1, NCT04501666; OLYMPIA 2, NCT04501679.
ETHICS STATEMENT
All participants or their guardians provided written informed consent.
Ständer S, Elmariah SB, Kwatra SG, Yosipovitch G, Pink AE, Cheong SY, et al. Rapid improvement of itch with nemolizumab in atopic dermatitis and prurigo nodularis phase 3 studies. J Eur Acad Dermatol Venereol. 2026;40:867–875. 10.1111/jdv.70250
Linked Article: K. Lukaschek et al. J Eur Acad Dermatol Venereol 2026;40:724–725. https://doi.org/10.1111/jdv.70389.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
REFERENCES
- 1. Liao V, Cornman HL, Ma E, Kwatra SG. Prurigo nodularis: new insights into pathogenesis and novel therapeutics. Br J Dermatol. 2024;190:798–810. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Stahl LS, Stander S, Zeidler C. New definitions and subtypes of chronic prurigo. Clin Dermatol. 2025;43:610–613. [DOI] [PubMed] [Google Scholar]
- 3. Silverberg JI, Wollenberg A, Reich A, Thaci D, Legat FJ, Papp KA, et al. Nemolizumab with concomitant topical therapy in adolescents and adults with moderate‐to‐severe atopic dermatitis (arcadia 1 and arcadia 2): Results from two replicate, double‐blind, randomised controlled phase 3 trials. Lancet. 2024;404:445–460. [DOI] [PubMed] [Google Scholar]
- 4. Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387:1109–1122. [DOI] [PubMed] [Google Scholar]
- 5. Pereira MP, Stander S. Assessment of severity and burden of pruritus. Allergol Int. 2017;66:3–7. [DOI] [PubMed] [Google Scholar]
- 6. Pereira MP, Hoffmann V, Weisshaar E, Wallengren J, Halvorson JA, Garcovich S, et al. Chronic nodular prurigo: Clinical profile and burden. A european cross‐sectional study. J Eur Acad Dermatol Venereol. 2020;34:2373–2383. [DOI] [PubMed] [Google Scholar]
- 7. Silverberg JI, Gelfand JM, Margolis DJ, Boguniewicz M, Fonacier L, Grayson MH, et al. Patient burden and quality of life in atopic dermatitis in us adults: A population‐based cross‐sectional study. Ann Allergy Asthma Immunol. 2018;121:340–347. [DOI] [PubMed] [Google Scholar]
- 8. Gwillim EC, Nattkemper L, Yosipovitch G. Impact of itch on sleep disturbance in patients with prurigo nodularis. Acta Derm Venereol. 2021;101:adv00424. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Pereira MP, Zeidler C, Wallengren J, Halvorsen JA, Weisshaar E, Garcovich S, et al. Chronic nodular prurigo: A european cross‐sectional study of patient perspectives on therapeutic goals and satisfaction. Acta Derm Venereol. 2021;101:adv00403. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Pereira MP, Zeidler C, Szymczak H, Bischoff C, Tsianakas A, Staender S, et al. Acceptability and perceived benefits of validated pruritus assessment instruments in the dermatological office and clinic: the perspectives of patients and physicians. J Eur Acad Dermatol Venereol. 2024;38:1973–1981. [DOI] [PubMed] [Google Scholar]
- 11. Kwatra SG, Rodriguez D, Dias‐Barbosa C, Budhiarso I, Fofana F, Vernon M, et al. Validation of the peak pruritus numerical rating scale as a patient‐reported outcome measure in prurigo nodularis. Dermatol Ther (Heidelb). 2023;13:2403–2416. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Stander S, Zeidler C, Pereira M, Szepietowski JC, McLeod M, Qin S, et al. Worst itch numerical rating scale for prurigo nodularis: A psychometric evaluation. J Eur Acad Dermatol Venereol. 2022;36:573–581. [DOI] [PubMed] [Google Scholar]
- 13. Datsi A, Steinhoff M, Ahmad F, Alam M, Buddenkotte J. Interleukin‐31: the “sitchy” cytokine in inflammation and therapy. Allergy. 2021;76:2982–2997. [DOI] [PubMed] [Google Scholar]
- 14. Kabashima K, Irie H. Interleukin‐31 as a clinical target for pruritus treatment. Front Med. 2021;8:638325. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Agelopoulos K, Pereira MP, Wiegmann H, Staender S. Cutaneous neuroimmune crosstalk in pruritus. Trends Mol Med. 2022;28:452–462. [DOI] [PubMed] [Google Scholar]
- 16. Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal A, et al. A sensory neuron‐expressed il‐31 receptor mediates t helper cell‐dependent itch: Involvement of trpv1 and trpa1. J Allergy Clin Immunol. 2014;133:448–460. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Kwatra SG, Yosipovitch G, Legat FJ, Reich A, Paul C, Simon D, et al. Phase 3 trial of nemolizumab in patients with prurigo nodularis. N Engl J Med. 2023;389:1579–1589. [DOI] [PubMed] [Google Scholar]
- 18. Silverberg JI, Pinter A, Alavi A, Lynde C, Bouaziz J‐D, Wollenberg A, et al. Nemolizumab is associated with a rapid improvement in atopic dermatitis signs and symptoms: Subpopulation (EASI ≥ 16) analysis of randomized phase 2b study. J Eur Acad Dermatol Venereol. 2021;35:1562–1568. [DOI] [PubMed] [Google Scholar]
- 19. Stander S, Yosipovitch G, Legat FJ, Reich a, Paul C, Simon D, et al. Efficacy and safety of nemolizumab in patients with moderate to severe prurigo nodularis: The olympia 1 randomized clinical phase 3 trial. JAMA Dermatol. 2025;161:147–156. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Stander S, Yosipovitch G, Lacour JP, Legat FJ, Paul C, Reich A, et al. Nemolizumab efficacy in prurigo nodularis: onset of action on itch and sleep disturbances. J Eur Acad Dermatol Venereol. 2022;36:1820–1825. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Yosipovitch G, Reaney M, Mastey V, Eckert L, Abbe A, Nelson L, et al. Peak pruritus numerical rating scale: Psychometric validation and responder definition for assessing itch in moderate‐to‐severe atopic dermatitis. Br J Dermatol. 2019;181:761–769. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Stander S, Fofana F, Dias‐Barbosa C, Rodriguez D, Budhiarso I, Jabbar‐Lopez JK, et al. The sleep disturbance numerical rating scale: Content validity, psychometric validation, and meaningful within‐patient change in prurigo nodularis. Dermatol Ther. 2023;13:1587–1602. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Puelles J, Fofana F, Rodriguez D, Silverberg JI, Wollenberg A, Dias Barbosa C, et al. Psychometric validation and responder definition of the sleep disturbance numerical rating scale in moderate‐to‐severe atopic dermatitis. Br J Dermatol. 2022;186:285–294. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Hay RJ, Johns NE, Williams HC, Bollinger IW, Dellavalle RP, Margolis DJ, et al. The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions. J Invest Dermatol. 2014;134:1527–1534. [DOI] [PubMed] [Google Scholar]
- 25. Karimkhani C, Dellavalle RP, Coffeng LE, Flohr C, Hay RJ, Langan SM, et al. Global skin disease morbidity and mortality: an update from the global burden of disease study 2013. JAMA Dermatol. 2017;153:406–412. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Zeidler C, Pereira MP, Huet F, Misery L, Steinbrink K, Staender S. Pruritus in autoimmune and inflammatory dermatoses. Front Immunol. 2019;10:1303. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Stander S, Kwatra SG, Silverberg JI, Simpson EL, Thyssen JP, Yosipovitch G, et al. Early itch response with abrocitinib is associated with later efficacy outcomes in patients with moderate‐to‐severe atopic dermatitis: subgroup analysis of the randomized phase iii jade compare trial. Am J Clin Dermatol. 2023;24:97–107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Guttman‐Yassky E, Teixeira HD, Simpson EL, Papp KA, Pangan AL, Blauvelt A, et al. Once‐daily upadacitinib versus placebo in adolescents and adults with moderate‐to‐severe atopic dermatitis (measure up 1 and measure up 2): Results from two replicate double‐blind, randomised controlled phase 3 trials. Lancet. 2021;397:2151–2168. [DOI] [PubMed] [Google Scholar]
- 29. Silverberg JI, Yosipovitch G, Simpson EL, Kim BS, Wu JJ, Eckert L, et al. Dupilumab treatment results in early and sustained improvements in itch in adolescents and adults with moderate to severe atopic dermatitis: Analysis of the randomized phase 3 studies solo 1 and solo 2, ad adol, and chronos. J Am Acad Dermatol. 2020;82:1328–1336. [DOI] [PubMed] [Google Scholar]
- 30. Yosipovitch G, Mollanazar N, Stander S, Kwatra SG, Kim BS, Laws E, et al. Dupilumab in patients with prurigo nodularis: two randomized, double‐blind, placebo‐controlled phase 3 trials. Nat Med. 2023;29:1180–1190. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Miron Y, Miller PE, Hughes C, Indersmitten T, Lerner EA, Cevikbas F. Mechanistic insights into the antipruritic effects of lebrikizumab, an anti‐il‐13 mab. J Allergy Clin Immunol. 2022;150:690–700. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.